The proposed work is ultimately directed to elucidating the biophysical basis of nervous dysfunction in demyelinating disease. Changes will be sought in the pattern of distribution of sodium channels, of potassium channels, and of sodium pumps in the nerve membrane during the processes of normal myelination (in the newborn animal) and of demyelination, produced experimentally in a number of ways. A variety of electrophysiological and pharmacological techniques will be used. Voltage-clamp experiments will be done to determine the Hodgkin-Huxley parameters for mammalian myelinated nerve at different temperatures. Based on the temperature dependences of the various parameters, computer simulation of the mammalian action potential at 37 C will be done. Sodium and potassium currents in voltage-clamp experiments will be used to examine sodium and potassium channels. The sensitivity of the compound action potential to 4-aminopyridine will be used to study potassium channels in situations (e.g. demyelination) where voltage clamping is not feasible. The electrophysiological consequence of myelination will be examined experimentally. Labelled saxitoxin will be used as a marker for sodium channels; a search will be made for a corresponding high affinity marker for potassium channels. Labelled ouabain will be used as a marker for sodium pumps.